The disclosure relates generally to the fields of tissue engineering and implantation.
Tissue engineering is a multidisciplinary field, in which practitioners aim to repair or regenerate lost or damaged tissues and organs in the body. A goal of tissue engineering workers is to design biomimetic scaffolds, which are three-dimensional engineered biomaterials that reproduce the mechanical and biochemical properties of natural tissue. Such materials should have desirable biological properties such that the biomaterials will, after implantation or application to a subject, become populated with the subject's cells (e.g., stem cells) which can promote formation of new extracellular matrix (ECM) and establishment of cell populations similar to or indistinguishable from those of tissue(s) or organ(s) that the materials are intended to resemble. The scaffolding material can remain in place indefinitely, and is preferably resorbable, such that it gradually disappears over time (e.g., through consumption of the scaffolding material by cells or by chemical decomposition over time).
Others have recognized the desirability of generating materials for use as bioscaffolds and/or bioadhesives. The following represent examples of such.
Strehin et al. have developed a chondroitin sulfate-polyethylene glycol (CS-PEG) adhesive hydrogel material for use as a bioscaffold (Strehin et al., 2010, Biomaterials 31:2788-2797). Carboxyl groups on CS chains were functionalized to yield CS-N-hydroxysuccinimide (CS-NHS). The CS-NHS molecule can react with primary amines to form amide bonds. However, long-term cell viability and differentiation within the matrix in the presence of reactive NHS groups was not reported and may be undesirable.
Wang et al. developed another tissue adhesive for cartilage regeneration based on an aldehyde-functionalized CS (Wang et al., 2007, Nature Mat. 6:385-392). Adhesion to a cartilage interface was demonstrated in vivo. However, only the survival of cells at the hydrogel-tissue interface, not within the matrix, was reported. Furthermore, injectability of such a system requires the implantation of methacrylate-functionalized CS macromers followed by in situ crosslinking. Potential problems with such in situ reactions include leaking of unreacted macromers into the physiological environment and heat generation.
Burke et al. developed a PEG-based system was developed that allows temperature-mediated release of sodium periodate, which is an oxidizing agent that converts the PEG chains into dialdehydes. Release of periodate induces attachment to surrounding tissues following implantation (Burke et al., 2007, Biomed. Mat. 2:203-210). While the idea of temperature sensitive release is appealing, the prospect of releasing sodium periodate, a potential toxic compound, in situ may limit the practical applicability of such compositions in ethical practice involving human or other subjects.
US patent application publication number 2002/0068087 discloses a bioadhesive for mucosa that is susceptible to enzymatic cleavage. The bioadhesive polymer described therein is synthesized by polymerization of vinyl monomers and crosslinked by a molecule that is degradable in vivo in mammals. This material is not injectable. US patent application publication number 2002/0092776 discloses a mucoadhesive material that exhibits thermally-triggered viscosification. The material is composed of a blend of poloxamers (polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymers) and polyacrylic acid. The material is disclosed to be useful for solubilization and local delivery of drugs. US patent application publication number 2006/0258788 discloses a bioadhesive polymer useful for coating biomedical electrodes. The disclosed material is composed of interpenetrating networks of two polymers, one containing carboxylic acids. Tissue adhesion by each of these three materials occurs primarily by way of hydrogen bonding. As a result, adhesion of these materials to tissue is relatively weak—likely too weak for many or most practical uses for implantation in animal subjects, especially in load-bearing situations (e.g., for implantation within or in place of intervertebral disc material in a human).
US patent application publication number 2008/0076852 discloses copolymers of poly(N-isopropylacrylamide) (and PEG copolymers thereof) with an amine-containing polymeric component. The copolymer is thermally responsive. Tissue adhesion of the copolymer occurs following injection of a dialdehyde (e.g., glutaraldehyde) into the gel. US patent application publication number 2010/0286786 discloses a multi-component system containing 1) an amine-containing polymer (e.g., a polyethylene imine), 2) a hydrophilic polymer (e.g., a PEG or a poly(vinyl alcohol)), and 3) a dialdehyde (e.g., glutaraldehyde). Owing to the potential for significant toxicity, the materials in these applications may be inappropriate for tissue engineering applications.
Significant shortcoming of some previously known scaffolding materials include undesirable toxicity and post-implantation/-application dislocation of the material from its original site. Such dislocation can contribute to failure of the material and its resident cells to integrate with surrounding host tissue, thereby inhibiting or preventing reestablishment of normal, hybrid, or replacement tissue at the desired body location. Such shortcomings could be avoided if the scaffolding material could be better secured at the site of application or implantation. The present disclosure describes materials which do not exhibit these shortcomings, at least to the degree they are exhibited by many previously-known materials.
Bioadhesive polymers are natural or synthetic materials that have been traditionally used for soft tissue repair, such wound closure, achieving hemostasis after a surgical procedure, or fistula repair. Bioadhesive materials can supplement the use of sutures or replace them altogether.
Fibrin adhesives are bioadhesives that act as a hemostatic plug by mimicking the last stage of blood clotting. The clot is resorbed within days or weeks allowing healing to occur at the site of adhesion. Because they are natural materials, fibrin sealants are completely biocompatible (Spotnitz et al., 2005, J. Long-Term Effects Med. Implants 15:245-270). However, the main drawback to this class of adhesives is a low cohesive strength (Siedentop et al., 1998, Laryngoscope 98:731-733; Sierra et al., 1992. J. Appl. Biomater. 3:147-151).
Another major group of bioadhesives known for its improved strength over fibrin is based on glutaraldehyde. Glutaraldehyde is an aliphatic organic molecule with aldehyde groups at each end. The di-aldehydes are able to react readily with the amines on proteins of the tissue extracellular matrix, via a Schiff's base reaction (Guibal et 11., 1999, Int. J. Biol. Macromol. 24:49-59), resulting in covalent crosslinks. Despite its high adhesive strength, inflammatory responses have been associated with glutaraldehyde application and have been ascribed to its cytotoxicity (Chang et al., 2002, Biomaterials 23:2447-2457; Fürst et al., 2005, Ann. Thorac. Surg. 79:1522-1529).
An unmet need exists at the intersection of bioadhesives and tissue engineering for a polymer that can form a strong bond with tissue and also support long-term cell survival. The subject matter disclosed herein addresses this need.